9-131072668-G-C

Variant names:

• chr9-131072668-G-C
• rs146221263
• NM_006059.4:c.3250G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_006059.4(LAMC3):​c.3250G>C​(p.Glu1084Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00508 in 1,611,370 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E1084K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (35 hom.)
• Consequence: LAMC3 NM_006059.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:12
• Conservation: PhyloP100: 1.49
• Publications: 6 publications found

Genes affected

LAMC3 (HGNC:6494): (laminin subunit gamma 3) Laminins, a family of extracellular matrix glycoproteins, are the major noncollagenous constituent of basement membranes. They have been implicated in a wide variety of biological processes including cell adhesion, differentiation, migration, signaling, neurite outgrowth and metastasis. Laminins are composed of 3 non identical chains: laminin alpha, beta and gamma (formerly A, B1, and B2, respectively) and they form a cruciform structure consisting of 3 short arms, each formed by a different chain, and a long arm composed of all 3 chains. Each laminin chain is a multidomain protein encoded by a distinct gene. Several isoforms of each chain have been described. Different alpha, beta and gamma chain isomers combine to give rise to different heterotrimeric laminin isoforms which are designated by Arabic numerals in the order of their discovery, i.e. alpha1beta1gamma1 heterotrimer is laminin 1. The biological functions of the different chains and trimer molecules are largely unknown, but some of the chains have been shown to differ with respect to their tissue distribution, presumably reflecting diverse functions in vivo. This gene encodes the gamma chain isoform laminin, gamma 3. The gamma 3 chain is most similar to the gamma 1 chain, and contains all the 6 domains expected of the gamma chain. It is a component of laminin 12. The gamma 3 chain is broadly expressed in skin, heart, lung, and the reproductive tracts. In skin, it is seen within the basement membrane of the dermal-epidermal junction at points of nerve penetration. Gamma 3 is also a prominent element of the apical surface of ciliated epithelial cells of lung, oviduct, epididymis, ductus deferens, and seminiferous tubules. The distribution of gamma 3-containing laminins along ciliated epithelial surfaces suggests that the apical laminins are important in the morphogenesis and structural stability of the ciliated processes of these cells. [provided by RefSeq, Aug 2011]

LAMC3 Gene-Disease associations (from GenCC):

• occipital pachygyria and polymicrogyria

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Illumina, Orphanet
• complex neurodevelopmental disorder

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005625963).
• BP6: Variant 9-131072668-G-C is Benign according to our data. Variant chr9-131072668-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194958.
• BS2: High Homozygotes in GnomAdExome4 at 35 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006059.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	NM_006059.4	MANE Select	c.3250G>C	p.Glu1084Gln	missense	Exon 19 of 28	NP_006050.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LAMC3	ENST00000361069.9	TSL:2 MANE Select	c.3250G>C	p.Glu1084Gln	missense	Exon 19 of 28	ENSP00000354360.4	Q9Y6N6
	LAMC3	ENST00000868026.1		c.3250G>C	p.Glu1084Gln	missense	Exon 19 of 28	ENSP00000538085.1
	LAMC3	ENST00000955224.1		c.3250G>C	p.Glu1084Gln	missense	Exon 19 of 28	ENSP00000625283.1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152120 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00111

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00380

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00663

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00544

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00341 AC: 843 AN: 247176 AF XY: 0.00364

Gnomad AFR exome AF: 0.000693

Gnomad AMR exome AF: 0.00233

Gnomad ASJ exome AF: 0.00422

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000802

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00349

GnomAD4 exome AF: 0.00525 AC: 7663 AN: 1459132 Hom.: 35 Cov.: 36 AF XY: 0.00537 AC XY: 3896 AN XY: 725758

African (AFR) AF: 0.000718 AC: 24 AN: 33420

American (AMR) AF: 0.00220 AC: 98 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 89 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00530 AC: 455 AN: 85914

European-Finnish (FIN) AF: 0.000829 AC: 44 AN: 53048

Middle Eastern (MID) AF: 0.00601 AC: 26 AN: 4326

European-Non Finnish (NFE) AF: 0.00592 AC: 6585 AN: 1111808

Other (OTH) AF: 0.00568 AC: 342 AN: 60204

GnomAD4 genome AF: 0.00347 AC: 529 AN: 152238 Hom.: 0 Cov.: 32 AF XY: 0.00341 AC XY: 254 AN XY: 74446

African (AFR) AF: 0.00111 AC: 46 AN: 41552

American (AMR) AF: 0.00379 AC: 58 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10608

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00543 AC: 369 AN: 67992

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00439 Hom.: 0

Bravo AF: 0.00317

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00329 AC: 399

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.00616

EpiControl AF: 0.00600

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	6	not provided (7)
-	-	2	not specified (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	LAMC3-related disorder (1)
-	-	1	Left ventricular noncompaction (1)
-	-	1	Occipital pachygyria and polymicrogyria (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	4.2
DANN	Benign	0.92
DEOGEN2	Benign	0.020	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		1.5
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.050
Sift	Benign	0.31	T
Sift4G	Benign	0.45	T
Polyphen		0.41	B
Vest4		0.30
MVP		0.42
MPC		0.48
ClinPred		0.0053	T
GERP RS		1.1
Varity_R		0.043
gMVP		0.39
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs146221263; hg19: chr9-133948055;